Periodontal diseases are multifactorial in nature.

While microbial and other environmental factors are believed to initiate and modulate periodontal disease progression, there now exist strong supporting data that genetic polymorphisms play a role in the predisposition to and progression of periodontal diseases. Variations in any number or combination of genes that control the development of the periodontal tissues or the competency of the cellular and humoral immune systems could affect an individual's risk for disease. A corollary of this realization is that if the genetic basis of periodontal disease susceptibility can be understood, such information may have diagnostic and therapeutic value. This review aims to update the clinician about various genetic polymorphisms associated with periodontal diseases to aid in a better approach to the condition in the future.

Periodontitis is defined as an inflammatory disease of the supporting tissues of the teeth caused by specific microorganisms or groups of specific microorganisms, resulting in progressive destruction of the periodontal ligament and alveolar bone with pocket formation, recession, or both.

Periodontal diseases are multifactorial in nature. While microbial and other environmental factors are believed to initiate and modulate periodontal disease progression, there now exists strong supporting data that genetic and environmental risk factors play a role in the predisposition to and progression of periodontal diseases

Several features like cytokines, cell-surface receptors, chemokines, enzymes and others that are related to antigen recognition, the immune system, host response, among others, are determined by genetic components; polymorphisms of which may increase the susceptibility of an individual to periodontal diseases. Identifying genes and their polymorphisms can result in novel diagnostics for risk assessment, early detection of disease and individualized treatment approaches. Thus, genetic epidemiology, including knowledge of genetic polymorphisms, holds promise as one of the tools that may contribute to the understanding of periodontal disease.

In the past it was thought that periodontitis would eventually develop in subjects with a longstanding history of poor oral hygiene and gingivitis. It was recognized that only a portion of the variability of disease in the population could be explained by environmental factors alone. This variation must have been attributable to either unrecognized components of the environment or differences among individuals in their susceptibilities to disease. Epidemiologic studies as well as longitudinal clinical studies of the oral microbial flora supported the development of the theory that although microbial and environmental factors are required for periodontitis, the disease may have a genetic background. In a classic longitudinal study of the natural history of periodontitis, Loe et al (1986) found that a relatively small proportion of the population is at risk for developing severe forms of periodontitis suggested that not everybody is equally susceptible to periodontitis.

It was debated that if periodontitis was simply and solely caused by one or more specific periodontal pathogens, the disease should have developed in majority of subjects infected by these organisms. In contrast, periodontal pathogens showed a relatively high prevalence in subjects with gingivitis or minor periodontitis as compared to severe forms. Therefore, the existence of high-risk groups could not be explained by the microbiology alone. These high-risk groups represented around 10-15% of the population, in whom the disease quickly progressed from chronic gingivitis to destructive periodontitis. Most genetic research in periodontitis has now focused on gene polymorphisms that play a role in immunoregulation or metabolism, such as cytokines, cell-surface receptors, chemokines, enzymes and others that are related to antigen recognition.

Given the complex etiology and pathogenesis of periodontal diseases, variations in any number or combination of genes that control the development of the periodontal tissues or the competency of the cellular and humoral immune systems could affect an individual's risk for disease. Evidence for a genetic influence on periodontal diseases comes from multiple sources including familial aggregation and formal genetic studies of aggressive periodontitis, the association of periodontitis with certain Mendelian inherited diseases, and twin studies of chronic periodontitis.

Chronic periodontitis has been defined as an infectious disease resulting in inflammation within the supporting tissues of the teeth, progressive attachment loss, and bone loss. It is associated with the accumulation of plaque and calculus and generally has a slow to moderate rate of disease progression, but periods of more rapid destruction may be observed. The disease also may be described by the severity of disease as slight, moderate or severe based on the amount of clinical attachment loss. Although no clear genetic determinants have been described for patients with chronic periodontitis, a genetic predisposition to more aggressive periodontal breakdown in response to plaque and calculus accumulation may exist. Clinicians have long suspected that susceptibility to periodontitis differs among racial and ethnic groups. Investigations have utilized family studies of probands with chronic (adult) periodontitis or younger subjects with mild/incipient periodontitis.

The twin model is probably the most powerful method to study genetic aspects of periodontal diseases. Michalowicz and co-workers evaluated the periodontal condition (attachment loss, pocket depth, gingival index and plaque index) of 110 adult twin pairs with a mean age of 40 years. The results indicated that between 38% and 82% of the population variance for these measures may be attributed to genetic factors. In a subsequent study the authors estimated that chronic (adult) periodontitis hadapproximately 50% heritability, which was unaltered following adjustments for behavioural variables including smoking and utilization of dental care. In epidemiological studies in the Dutch population, it has been suggested that periodontitis aggregates in families. Kornman et al reported that a composite IL-1 genotype consisting of at least one copy of the more rare allele at both an IL-l and IL-1 loci was associated with severe periodontitis.

Karimbux et al (2012), in their meta-analysis, reported that IL1A and IL1B genetic variations are significant contributors to chronic periodontitis in Caucasians. From both the twin studies and familial studies it can be concluded that the basis for familial aggregation of periodontitis appears to be genetic rather than bacterial, environmental or behavioral in nature. The heritable component for periodontitis was not associated with behaviors such as smoking, utilization of dental care and oral hygiene habits. This implies that genes controlling biologic mechanisms, and not behaviors, mediate the genetic influence on disease.

Aggressive periodontitis is characterized by rapid rate of disease progression seen in an otherwise healthy individual, an absence of large accumulations of plaque and calculus and a family history of aggressive disease suggestive of a genetic trait. Marked aggregation of aggressive periodontitis within families is consistent with a genetic predisposition to this disease. One of the largest and most comprehensive segregation analysis for aggressive periodontitis has been performed by Marazita et al (1994). It was suggested by the authors that the most likely mode of inheritance was autosomal dominant in both African-American and Caucasian kindred, with 70% penetrance in AfricanAmericans and 73% in Caucasians. Studies have also been conducted on linkage analysis of candidate regions which lie within or near genes that code for enzymes or regulatory molecules that are likely to be involved in the pathogenesis of disease.

The human leukocyte antigens (HLA) have been considered to be candidate markers for aggressive periodontitis because they are involved in regulating immune responses. Two antigens that appear to be consistently associated are HLA-A9 and B15.

The risk of disease in subjects with HLA-A9 or B15 is about 1.5 to 3.5 times greater than in those lacking these antigens.
In contrast, the HLA-A2 appears to be less prevalent in aggressive periodontitis patients than controls, suggesting that this antigen somehow may be protective. An IL1B allele has been reported to be in linkage disequilibrium with generalized aggressive periodontitis, suggesting that at least one disease allele is at or very close to this IL1B polymorphism (2q13)

Another study concluded that in West European Caucasians, the Asp299Gly TLR4 gene polymorphism was associated with a decreased risk of AgP but not CP . Promoter polymorphisms of the CD14 gene, however, did not influence susceptibility to inflammatory periodontitis in the population cohorts studied. Li et al provided evidence stating FokI polymorphism of vitamin D receptor gene might be associated with generalized aggressive periodontitis in Chinese patients. Most studies of aggressive periodontitis (or EOP) to date have had inadequate statistical power to resolve substantial genetic heterogeneity.

The most extensively studied of the monogenic conditions is the Papillon-Lefevre syndrome. It is inherited as anautosomal recessive trait. The classical clinical manifestations of Papillon-Lefevre syndrome are hyperkeratotic lesions of the skin, affecting the palmoplantar surfaces, and aggressive periodontitis, affecting the deciduous and permanent dentitions. In addition to defects in epithelium formation, reduced lymphocyte response in vitro and decreased chemotaxis and phagocytosis of neutrophils and monocytes have been reported in Papillon-Lefevre syndrome patients. Studies involving genome wide linkage scans of consanguineous families mapped the Papillon-Lefevre syndrome locus to the long arm of chromosome 11, with the gene encoding lysosomal protease cathepsin C.

This enzyme is expressed at high levels in many immune cells including polymorphonuclear leukocytes and macrophages and their precursors. It has been found that cathepsin C is expressed in areas of epithelium often affected by hyperkeratotic lesions such as palms, soles, knees and oral keratinized gingiva. Individuals displaying the Papillon-Lefevre syndrome phenotype are homozygous for the trait. Another syndrome described by Haim and Munk (1965) has only been observed in the descendents of a religious sect originally from India. This condition displays the same features of hyperkeratosis and severe aggressive periodontitis as Papillon-Lefevre syndrome, with the addition of arachnodactyly and a peculiar deformity of the terminal phalanges.

The Haim-Munk syndrome was also found to be linked to the cathepsin C gene.

Papillon-Lefevre syndrome and Haim-Munk syndrome are allelic variants of mutations of the cathepsin C gene.

Patients who respond poorly to periodontal treatment by continuing to lose clinical attachment are said to have refractory periodontitis. Neutrophils from refractory disease patients usually display some functional defect. Kobayashi et al tested the association between neutrophil immunoglobulin G receptor (FcR) polymorphisms and adult (now known as chronic) periodontitis in a Japanese population.

These polymorphisms, which reside in genes that encode receptors for the IgG isotypes, correlate with how efficiently PMNs are able to phagocytose opsonized antigens.
The frequency of FcR genotypes did not differ between chronic periodontitis patients and healthy controls.

Among patients, however, one allele (FcRIIIB-NA2) was found to be more prevalent in those who experienced recurrent disease .

Gingival enlargement is the overgrowth of the gingiva characterized by an expansion and accumulation of the connective tissue with occasional presence of increased number of cells. It is a form of periodontal disease which can be inherited (hereditary gingival fibromatosis (HGF), associated with other diseases characterizing a syndrome, caused by several factors, such as inflammation, leukemia, etc or induced as an adverse effect of systemic drugs, such as phenytoin, cyclosporine or nifedipine. The gingival enlargement results in both esthetic and functional problems for affected individuals. HGF, previously known as elephantiasis gingivae, hereditary gingival hyperplasia and hypertrophic gingiva, is traditionally considered an autosomal dominant disease.

HGF is a rare disease of infancy characterized by progressive gingival enlargement of normal color and firm consistency that is non-hemorrhagic and asymptomatic. HGF results in diastemas, malpositioning of teeth, prominent lips and open lip posture. The gingival enlargement does not directly affect the alveolar bone, the gingival swelling may increase the bacterial plaque accumulation, inducing periodontitis and bone resorption and halitosis. The first case was probably reported by Gross in 1856 and although over the past few years increasing efforts have been made to understand the genetic, molecular and cellular basis of the gingival enlargement of HGF patients, it has been impaired by the intense clinical, genetic and biologic heterogeneity of the disease.

Three different loci have been associated with the isolated form of HGF: two mapping to chromosome 2 (GINGF on 2p21-22 and GINGF3 on 2p22.3-p23.3), which do not overlap, and one mappping to chromosome 5 (GINGF2 on 5q13-q22). Of these loci, only the SOS1 (son of sevenless one) gene underlying the GINGF locus has been identified. The SOS1 mutation linked to HGF was observed in a large multigenerational Brazilian family segregating HGF as a highly penetrant autosomal dominant gene. The single insertion mutation, which causes a frame shift and a stop codon resulting in a truncated protein, was segregated in all affected patients and was not identified in unaffected family members or in control subjects.

Drug-induced gingival overgrowth has been seen in patients following intake of phenytoin, cyclosporine or nifedipine. Phenytoin, cyclosporine and nifedipine are all metabolized by the hepatic cytochrome P450 enzymes. Cytochrome P450 genes exhibit considerable polymorphism, which results in interindividual variation in drug levels. This inherited variation in metabolism of either drug may influence patient serum and tissue concentrations and hence their gingival response.

Another genetic marker that has been investigated in relation to drug-induced gingival overgrowth is the human lymphocyte antigen expression (HLA).
Several studies have reported on the relationship between HLA expression and the incidence of drug induced gingival overgrowth.

A study reported that patients who expressed HLA-DR1 are afforded some degree of protection against gingival overgrowth whilst HLA-DR2 may increase the development of this unwanted effect. To date only HLA-B37 has been identified as a significant risk factor after correction for the effect of multiple significance testing and these patients are protected in some way from the effects of gingival overgrowth. The concept of molecular mimicry in the wider field of periodontal disease or an effect on lymphocyte function have been postulated as the mechanisms that may tie HLA antigens to gingival overgrowth.

With recent evidence implicating the role of periodontal disease on systemic health, an understanding of the potential role of genetic polymorphisms on periodontal disease may help in modifying our treatment plan to improve periodontal health, as well as, general health.

Emerging data strongly suggest that host genetic factors are important determinants for periodontitis susceptibility.
Genetic tests may prove useful for identifying patients who are most likely to develop periodontal disease, suffer from recurrent disease or suffer tooth loss as a result of periodontal disease. Genetic polymorphisms also result in the development of monogenic syndromes of which periodontal diseases are an important sign.

Recently, genome-wide association studies using single nucleotide polymorphisms or microsatellite polymorphisms have become realistic due to the development of promising high-throughput and cost-effective single nucleotide polymorphism typing. As suggested by Tamiya et al, microsatellite-based genome-wide association analysis complemented by end-stage single nucleotide polymorphism typing will be an interesting strategy for genetic dissection of multifactorial pathologies such as common diseases, including periodontitis. Future strategies for the utilization of genetic polymorphisms in Periodontics will need to consider at least two factors. The first is to perform large-scale genetic analyses in diverse populations using as many target genes and subjects as reasonably possible.

Secondly, there needs to be a development of new statistical analytical methods to combine both genetic and environmental factors. To achieve these goals, multicenter research studies will be needed to maximize cost- and time-effectiveness.